Method for treating COPD

ABSTRACT

A method for treating COPD is disclosed comprising administering compounds of Formula (I)                    
     wherein the terms R 1 , R 3 , X, X 2  and Z are herein defined.

This application claims benefit of provisional application Ser. No.60/070,718 filed Jan. 7, 1998 and Ser. No. 60/106,908 filed Oct. 28,1998.

FIELD OF THE INVENTION

The present invention relates to the use of certain compounds fortreating chronic obstructive pulmonary disease (COPD).

BACKGROUND OF THE INVENTION

Chronic obstructive pulmonary disease (COPD) is an umbrella termfrequently used to describe two conditions of fixed airways disease,chronic bronchitis and emphysema. Chronic bronchitis and emphysema aremost commonly caused by smoking; approximately 90% of patients with COPDare or were smokers. Although approximately 50% of smokers developchronic bronchitis, only 15% of smokers develop disabling airflowobstruction. Certain animals, particularly horses, suffer from COPD aswell.

The airflow obstruction associated with COPD is progressive, may beaccompanied by airway hyperreactivity, and may be partially reversible.Non-specific airway hyper-responsiveness may also play a role in thedevelopment of COPD and may be predictive of an accelerated rate ofdecline in lung function in smokers.

COPD is a significant cause of death and disability. It is currently thefourth leading cause of death in the United States and Europe. Treatmentguidelines advocate early detection and implementation of smokingcessation programs to help reduce morbidity and mortality due to thedisease. However, early detection and diagnosis has been difficult for anumber of reasons.

COPD takes years to develop and smokers often deny any ill effects fromsmoking, attributing the early warning signs of increased breathlessnessas a sign of age. Similarly, acute episodes of bronchitis often are notrecognized by the general practitioner as early signs of COPD. Manypatients exhibit features of more than one disease (e.g. chronicbronchitis or asthmatic bronchitis) making precise diagnosis achallenge, particularly in early disease. Also, many patients do notseek medical help until they are experiencing more severe symptomsassociated with reduced lung function, such as dyspnea, persistentcough, and sputum production. As a consequence, the vast majority ofpatients are not diagnosed or treated until they are in a more advancedstage of disease.

There is a need for a new approach to treating COPD. This inventionprovides one such approach.

SUMMARY OF THE INVENTION

This invention covers a method for the prophylaxis or treatment of COPDin a mammal by administering to a mammal in need thereor an effectiveamount of a compound of Formula (I) alone or in admixture with apharmaceutically acceptable excipient wherein Formula (I) comprises:

wherein:

R₁ is —(CR₄R₅)_(n)C(O)O(CR₄R₅)_(m)R₆, —(CR₄R₅)_(n)C(O)NR₄(CR₄R₅)_(m)R₆,—(CR₄R₅)_(n)O(CR₄R₅)_(m)R₆, or —(CR₄R₅)_(r)R₆ wherein the alkyl moietiesmay be optionally substituted with one or more halogens;

m is 0 to 2;

n is 1 to 4;

r is 0 to 6;

R₄ and R₅ are independently selected from hydrogen or a C₁₋₂ alkyl;

R₆ is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl,aryloxyC₁₋₃ alkyl, halo substituted aryloxyC₁₋₃ alkyl, indanyl, indenyl,C₇₋₁₁ polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl,pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl,C₃₋₆ cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl and heterocyclic moieties may beoptionally substituted by OH, 1 to 3 methyl groups or one ethyl group;

provided that:

a) when R₆ is hydroxyl, then m is 2; or

b) when R₆ is hydroxyl, then r is 2 to 6; or

c) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or

d) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;

e) when n is 1 and m is 0, then R₆ is other than H in—(CR₄R₅)_(n)O(CR₄R₅)_(m)R₆;

X is YR₂, halogen, nitro, NR₄R₅, or formyl amine;

Y is O or S(O)_(m)′;

m′ is 0, 1, or 2;

X₂ is O or NR₈;

X₃ is hydrogen or X;

X₄ is

X₅ is H, R₉, OR₈, CN, C(O)R₈, C(O)OR₈, C(O)NR₈R₈, or NR₈R₈;

R₂ is independently selected from the group consisting of —CH₃ and—CH₂CH₃ optionally substituted by 1 or more halogens;

s is 0 to 4;

R₃ is hydrogen, halogen, C₁₋₄ alkyl, CH₂NHC(O)C(O)NH₂, halo-substitutedC₁₋₄ alkyl, —CH═CR_(8′)R_(8′), cyclopropyl optionally substituted byR_(8′), CN, OR₈, CH₂OR₈, NR₈R₁₀, CH₂NR₈R₁₀, C(Z′)H, C(O)OR₈, C(O)NR₈R₁₀,or C≡CR_(8′),

Z′ is O, NR₉, NOR₈, NCN, C(—CN)₂, CR₈CN, CR₈NO₂, CR₈C(O)OR₈,CR₈C(O)NR₈R₈, C(—CN)NO₂, C(—CN)C(O)OR₉, or C(—CN)C(O)NR₈R₈;

Z is C(Y′)R₁₄, C(O)OR₁₄, C(Y′)NR₁₀R₁₄, C(NR₁₀)NR₁₀R₁₄, CN, C(NOR₈)R₁₄,C(O)NR₈NR₈C(O)R₈, C(O)NR₈NR₁₀R₁₄, C(NOR₁₄)R₈, C(NR₈)NR₁₀R₁₄,C(NR₁₄)NR₈R₈, C(NCN)NR₁₀R₁₄, C(NCN)SR₉, (2-, 4- or 5-imidazolyl), (3-,4- or 5-pyrazolyl), (4- or 5-triazolyl[1,2,3]), (3- or5-triazolyl[1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or5-isoxazolyl), (3- or 5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]),(2-thiadiazolyl[1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or5-imidazolidinyl); wherein all of the heterocylic ring systems may beoptionally substituted one or more times by R₁₄;

the dotted line in formula (a) represents a single or double bond;

Y′ is O or S;

R₇ is —(CR₄R₅)_(q)R₁₂ or C₁₋₆ alkyl wherein the R₁₂ or C₁₋₆ alkyl groupis optionally substituted one or more times by C₁₋₂ alkyl optionallysubstituted by one to three fluorines, —F, —Br, —Cl, —NO₂, —NR₁₀R₁₁,—C(O)R₈, —C(O)OR₈, —OR₈, —CN, —C(O)NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —OC(O)R₈,—NR₁₀C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀C(O)OR₉, —NR₁₀C(O)R₁₃,—C(NR₁₀)NR₁₀R₁₁, —C(NCN)NR₁₀R₁₁, —C(NCN)SR₉, —NR₁₀C(NCN)SR₉,—NR₁₀C(NCN)NR₁₀R₁₁, —NR₁₀S(O)₂R₉, —S(O)_(m′)R₉, —NR₁₀C(O)C(O)NR₁₀R₁₁,—NR₁₀C(O)C(O)R₁₀, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl,or tetrazolyl;

q is 0, 1, or 2;

R₁₂ is C₃₋₇ cycloalkyl, (2-, 3- or 4-pyridyl), pyrirnidyl, pyrazolyl,(1- or 2-imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl,piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), (4- or5-thiazolyl), quinolinyl, naphthyl, or phenyl;

R₈ is independently selected from hydrogen or R₉;

R₈′ is R₈ or fluorine;

R₉ is C₁₋₄ alkyl optionally substituted by one to three fluorines;

R₁₀ is OR₈ or R₁₁;

R₁₁ is hydrogen, or C₁₋₄ alkyl optionally substituted by one to threefluorines; or when R₁₀ and R₁₁ are as NR₁₀R₁₁ they may together with thenitrogen form a 5 to 7 membered ring optionally containing at least oneadditional heteroatom selected from O, N, or S;

R₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl,oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings isconnected through a carbon atom and each may be unsubstituted orsubstituted by one or two C₁₋₂ alkyl groups;

R₁₄ is hydrogen or R₇; or when R₁₀ and R₁₄ are as NR₁₀R₁₄ they maytogether with the nitrogen form a 5 to 7 membered ring optionallycontaining one or more additional heteroatoms selected from O, N, or S;

provided that:

f) when R₁₂ is N-pyrazolyl, N-imnidazolyl, N-triazolyl, N-pyrrolyl,N-piperazinyl, N-piperidinyl, or N-morpholinyl, then q is not 1; or

g) when X₂R₁ is OCF₂H or OCF₃, X is OCF₂H or OCF₃, X₃ is H, s is zero,X₅ is H, Z is C(O)OR₁₄ and R₁₄ is C₁₋₇ unsubstituted alkyl, then R₃ isother than H;

or the pharmaceutically acceptable salts thereof.

In a second aspect, this invention relates to the use of a compound ofFormula (II) for treating COPD in a mammal, particularly a human,wherein Formula (II) is defined as follows:

wherein:

R₁ is —(CR₄R₅)_(n)C(O)O(CR₄R₅)_(m)R₆, —(CR₄R₅)_(n)C(O)NR₄(CR₄R₅)_(m)R₆,—(CR₄R₅)_(n)O(CR₄R₅)_(m)R₆, or —(CR₄R₅)_(r)R₆ wherein the alkyl moietiesunsubstituted or substituted with one or more halogens;

m is 0 to 2;

n is 0 to 4;

r is 0 to 6;

R₄ and R₅ are independently selected hydrogen or C₁₋₂ alkyl;

R₆ is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl,aryloxyC₁₋₃ alkyl, halo substituted aryloxyC₁₋₃ alkyl, indanyl, indenyl,C₇₋₁₁ polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl,pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl,C₃₋₆ cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl or heterocyclic moiety is unsubstituted orsubstituted by 1 to 3 methyl groups, one ethyl group, or an hydroxylgroup;

provided that:

a) when R₆ is hydroxyl, then m is 2; or

b) when R₆ is hydroxyl, then r is 2 to 6; or

c) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or

d) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;

e) when n is 1 and m is 0, then R₆ is other than H in—(CR₄R₅)_(n)O(CR₄R₅)_(m)R₆;

X is YR₂, fluorine, NR₄R₅, or formyl amine;

Y is O or S(O)_(m′);

m′ is 0, 1, or 2;

X₂ is O or NR₈;

X₃ is hydrogen or X;

X₄ is H, R₉, OR₈, CN, C(O)R₈, C(O)OR₈, C(O)NR₈R₈, or NR₈R₈;

R₂ is independently selected from —CH₃ or —CH₂CH₃ optionally substitutedby 1 or more halogens;

s is 0 to 4;

W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynylof 2 to 6 carbon atoms;

R₃ is COOR₁₄, C(O)NR₄R₁₄ or R₇;

Z is OR₁₄, OR₁₅, SR₁₄, S(O)_(m′)R₇, S(O)₂NR₁₀R₁₄, NR₁₀R₁₄, NR₁₄C(O)R₉,NR₁₀C(Y′)R₁₄, NR₁₀C(O)OR₇, NR₁₀C(Y′)NR₁₀R₁₄, NR₁₀S(O)₂NR₁₀R₁₄,NR₁₀C(NCN)NR₁₀R₁₄, NR₁₀S(O)₂R₇, NR₁₀C(CR₄NO₂)NR₁₀R₁₄, NR₁₀C(NCN)SR₉,NR₁₀C(CR₄NO₂)SR₉, NR₁₀C(NR₁₀)NR₁₀R₁₄, NR₁₀C(O)C(O)NR₁₀R₁₄, orNR₁₀C(O)C(O)OR₁₄;

Y′ is O or S;

R₇ is —(CR₄R₅)_(q)R₁₂ or C₁₋₆ alkyl wherein the R₁₂ or C₁₋₆ alkyl groupis unsubstituted or substituted one or more times by methyl or ethylunsubstituted or substituted by 1-3 fluorines, —F, —Br, —Cl, —NO₂,—NR₁₀R₁₁, —C(O)R₈, —CO₂R₈, —O(CH₂)₂₋₄OR₈, —O(CH₂)_(q)R₈, —CN,—C(O)NR₁₀R₁₁, —O(CH₂)_(q) C(O)NR₁₀R₁₁, —O(CH₂)_(q)C(O)R₉,—NR₁₀C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀C(O)OR₉, —NR₁₀C(O)R₁₃,—C(NR₁₀)NR₁₀R₁₁, —C(NCN)NR₁₀R₁₁, —C(NCN)SR₉, —NR₁₀C(NCN)SR₉,—NR₁₀C(NCN)NR₁₀R₁₁, —NR₁₀S(O)₂R₉, —S(O)_(m′)R₉, —NR₁₀C(O)C(O)NR₁₀R₁₁,—NR₁₀C(O)C(O)R₁₀, or R₁₃;

q is 0, 1, or 2;

R₁₂ is R₁₃, C₃-C₇ cycloalkyl, or an unsubstituted or substituted aryl orheteroaryl group selected from the group consisting of (2-, 3- or4-pyridyl), pyrimidinyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl,piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl),quinolinyl, naphthyl, and phenyl;

R₈ is independently selected from hydrogen or R₉;

R₉ is C₁₋₄ alkyl optionally substituted by one to three fluorines;

R₁₀ is OR₈ or R₁₁;

R₁₁is hydrogen, or C₁₋₄ alkyl unsubstituted or substituted by one tothree fluorines; or when R₁₀ and R₁₁ are as NR₁₀R₁₁ they may togetherwith the nitrogen form a 5 to 7 membered ring comprised of carbon orcarbon and one or more additional heteroatoms selected from O, N, or S;

R₁₃ is a substituted or unsubstituted heteroaryl group selected from thegroup consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl,triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl,isoxazolyl, oxadiazolyl, and thiadiazolyl, and where R₁₃ is substitutedon R₁₂ or R₁₃ the rings are connected through a carbon atom and eachsecond R₁₃ ring may be unsubstituted or substituted by one or two C₁₋₂alkyl groups unsubstituted or substituted on the methyl with 1 to 3fluoro atoms;

R₁₄ is hydrogen or R₇; or when R₈ and R₁₄ are as NR₈R₁₄ they maytogether with the nitrogen form a 5 to 7 membered ring comprised ofcarbon or carbon and one or more additional heteroatoms selected from O,N, or S;

R₁₅ is C(O)R₁₄, C(O)NR₈R₁₄, S(O)_(q)NR₈R₁₄ or S(O)_(q)R₇ where q is 0, 1or 2;

provided that:

(f) R₇ is not C₁₋₄ alkyl unsubstituted or substituted by one to threefluorines;

or the pharmaceutically acceptable salts thereof.

In a further aspect, this invention relates to a pharmaceuticallyacceptable composition for treating COPD comprising a pharmaceuticallyacceptable excipient and between about 1 and 60 mg of a compound ofFormula (I) or (II) at least once daily.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to the use of compounds of Formulas (I) or (II)and to pharmaceutical compositions comprising a compound of Formulas (I)or (II) and a pharmaceutically acceptable carrier or diluent, fortreating COPD in a mammal, particularly a human, suffering from COPD.The drug may have use in the prophylaxis of the phenomena associatedwith COPD before clinical manifestation of the disease in a mammal,particularly a human.

COPD is characterized by a chronic inflammatory process in the lungmarked by in increase in the activation and/or number of alveolarmacrophages, CD8⁺ T-cells and neutrophils. Most notably with respect tothe therapy of COPD is the ability to alter the trafficking andactivation of neutrophils. The neutrophil is believed to play a centralrole in the pathophysiology of COPD. Neutrophil activation results inthe release of a number of inflammatory mediators and proteinases, mostimportantly neutrophil elastase which contributes to the progressivefibrosis, airway stenosis and destruction of the lung parenchyma,leading to an accelerated decline in airway function. Neutrophilelastase is also a powerful mucus secretagogue and thus may contributeto the characteristic mucus hypersecretion that characterizes COPD. Thecompounds of this invention have marked effects on neutrophil activity,inhibiting neutrophil chemotaxis and degranulation in vitro. In animalmodels, the instant compounds reduce neutrophil extravasation from thecirculation, pulmonary sequestration and the edematous responses to anumber inflammatory insults in vivo.

Additional activities that may contribute to the therapeutic activity ofPDE4 inhibitors in COPD include bronchodilation and modulation ofpulmonary neuronal activity. Although the degree of reversibility ofreduced airway flow is low in COPD, a small increase may have an acutepositive effect, as well as a gradual reduction in the slope of thedecline which may result in a profound effect on quality of life forCOPD patients. The ability of inhaled muscarinc antagonists to produceclinically meaningful improvements in pulmonary function in COPD, atleast acutely, suggest that a large component of the reversible airwaysobstruction in this disease is associated with a dysregulation ofpulmonary nerves. Although not studied in detail as yet, PDE4 inhibitorsmay also modulate the activity of airway epithelial cells, a rich sourceof proinflammatory mediators that are released upon environmental insult(e.g., smoke), and inhibit vascular smooth muscle hyperplasia, astructural change in end stage COPD that is associated with right heartfailure.

The preferred compounds for use in this invention are defined asfollows:

When R₁ for the compounds of the Formula (I) is an alkyl substituted by1 or more halogens, the halogens are preferably fluorine and chlorine,more preferably a C₁₋₄ alkyl substituted by 1 or more fluorines. Thepreferred halo-substituted alkyl chain length is one or two carbons, andmost preferred are the moieties —CF₃, —CH₂F, —CHF₂, —CF₂CHF₂, —CH₂CF₃,and —CH₂CHF₂. Preferred R₁ substitutents for the compounds of theFormula (I) are CH₂-cyclopropyl, CH₂—C₅₋₆ cycloalkyl, C₄₋₆ cycloalkyl,C₇₋₁₁ polycycloalkyl, (3- or 4-cyclopentenyl), phenyl,tetrahydrofuran-3-yl, benzyl or C₁₋₂ alkyl optionally substituted by 1or more fluorines, —(CH₂)₁₋₃C(O)O(CH₂)₀₋₂CH₃, —(CH₂)₁₋₃O(CH₂)₀₋₂CH₃, and—(CH₂)₂₋₄OH.

When the R₁ term contains the moiety (CR₄R₅), the R₄ and R₅ terms areindependently hydrogen or alkyl. This allows for branching of theindividual methylene units as (CR₄R₅)_(n) or (CR₄R₅)_(m); each repeatingmethylene unit is independent of the other, e.g., (CR₄R₅)_(n) wherein nis 2 can be —CH₂CH(—CH₃)—, for instance. The individual hydrogen atomsof the repeating methylene unit or the branching hydrocarbon canoptionally be substituted by fluorine independent of each other toyield, for instance, the preferred R₁ substitutions, as noted above.

When R₁ is a C₇₋₁₁ polycycloalkyl, examples are bicyclo[2.2.1]-heptyl,bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1.0^(2,6)]decyl,etc. additional examples of which are described in Saccamano et al., WO87/06576, published Nov. 5, 1987, whose disclosure is incorporatedherein by reference in its entirety.

Z is preferably C(O)R₈, C(O)OR₈, C(O)NR₈R₈, C(NR₈)NR₈R₈, CN, C(NOR₈)R₈,C(O)NR₈NR₈C(O)R₈, C(NR₈)NR₈R₈, C(NCN)NR₈R₈, C(NCN)SR₉, (1-, 4- or5-{R₈}-2-imidazolyl), (1-, 4- or 5-{R₈}-3-pyrazolyl), (1-, 2- or5-{R₈}-4-triazolyl[1,2,3]), (1-, 2-, 4- or 5-{R₈}-3-triazolyl[1,2,4]),(1- or 2-{R₈}-5-tetrazolyl), (4- or 5-{R₈}-2-oxazolyl), (3- or4-{R₈}-5-isoxazolyl), (3-{R₈}-5-oxadiazolyl[1,2,4]),(5-{R₈}-3-oxadiazolyl[1,2,4]), (5-{R₈}-2-oxadiazolyl[1,3,4]),(5-{R₈}-2-thiadiazolyl[1,3,4]), (4- or 5-{R₈}-2-thiazolyl), (4- or5-{R₈}-2-oxazolidinyl), (4- or 5-{R₈}-2-thiazolidinyl), (1-, 4- or5-{R₈}-2-imidazolidinyl); most preferred are those compounds wherein theR₈ group of Z is R₄.

X₅ is preferably hydrogen, C₁₋₂ alkyl optionally substituted by one tothree fluorines, OR₈, CN, C(O)R₈, C(O)OR₈, C(O)NR₈R₈, or NR₈R₈.

Preferred X groups for Formula (I) are those wherein X is YR₂ and Y isoxygen. The preferred X₂ group for Formula (I) is that wherein X₂ isoxygen. The preferred X₃ group for Formula (I) is that wherein X₃ ishydrogen. Preferred R₂ groups, where applicable, are C₁₋₂ alkyloptionally substituted by 1 or more halogens. The halogen atoms arepreferably fluorine and chlorine, more preferably fluorine. Morepreferred R₂ groups are those wherein R₂ is methyl, or thefluoro-substituted alkyls, specifically a C₁₋₂ alkyl, such as a —CF₃,—CHF₂, or —CH₂CHF₂ moiety. Most preferred are the —CHF₂ and —CH₃moieties.

Preferred R₃ moieties are C(O)NH₂, C≡CR₈, CN, C(Z′)H, CH₂OH, CH₂F, CF₂H,and CF₃. More preferred are —C≡CH and CN. Z′ is preferably O or NOR₈.

Preferred R₇ moieties include optionally substituted—(CH₂)₁₋₂(cyclopropyl), —(CH₂)₀₋₂(cyclobutyl), —(CH₂)₀₋₂(cyclopentyl),—(CH₂)₀₋₂(cyclohexyl), —(CH₂)₀₋₂(2-, 3- or 4-pyridyl),—(CH₂)₁₋₂(2-imidazolyl), —(CH₂)₂(4-morpholinyl), —(CH₂)₂(4-piperazinyl),—(CH₂)₁₋₂(2-thienyl), —(CH₂)₁₋₂(4-thiazolyl), and —(CH₂)₀₋₂phenyl;

Preferred rings when R₁₀ and R₁₁ in the moiety —NR₁₀R₁₁ together withthe nitrogen to which they are attached form a 5 to 7 membered ringoptionally containing at least one additional heteroatom selected fromO, N, or S include, but are not limited to 1-imidazolyl,2-(R₈)-1-imidazolyl, 1-pyrazolyl, 3-(R₈)-1-pyrazolyl, 1-triazolyl,2-triazolyl, 5-(R₈)-1-triazolyl, 5-(R₈)-2-triazolyl,5-(R₈)-1-tetrazolyl, 5-(R₈)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl,morpholinyl, piperazinyl, 4-(R₈)-1-piperazinyl, or pyrrolyl ring.

Preferred rings when R₁₀ and R₁₄ in the moiety —NR₁₀R₁₄ together withthe nitrogen to which they are attached may form a 5 to 7 membered ringoptionally containing at least one additional heteroatom selected fromO, N, or S include, but are not limited to 1-imidazolyl, 1-pyrazolyl,1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl,piperazinyl, and pyrrolyl. The respective rings may be additionallysubstituted, where applicable, on an available nitrogen or carbon by themoiety R₇ as described herein for Formula (I). Illustrations of suchcarbon substitutions includes, but are not limited to,2-(R₇)-1-imidazolyl, 4-(R₇)-1-imidazolyl, 5-(R₇)-1-imidazolyl,3-(R₇)-1-pyrazolyl, 4-(R₇)-1-pyrazolyl, 5-(R₇)-1-pyrazolyl,4-(R₇)-2-triazolyl, 5-(R₇)-2-triazolyl, 4-(R₇)-1triazolyl,5-(R₇)-1-triazolyl, 5-(R₇)-1-tetrazolyl, and 5-(R₇)-2-tetrazolyl.Applicable nitrogen substitution by R₇ includes, but is not limited to,1-(R₇)-2-tetrazolyl, 2-(R₇)-1-tetrazolyl, 4-(R₇)-1-piperazinyl. Whereapplicable, the ring may be substituted one or more times by R₇.

Preferred groups for NR₁₀R₁₄ which contain a heterocyclic ring are5-(R₁₄)-1-tetrazolyl, 2-(R₁₄)-1-imidazolyl, 5-(R₁₄)-2-tetrazolyl, or4-(R₁₄)-1-piperazinyl.

Preferred rings for R₁₃ include (2-, 4- or 5-imidazolyl), (3-, 4- or5-pyrazolyl), (4- or 5-triazolyl[1,2,3]), (3- or 5-triazolyl[1,2,4]),(5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]), (2-thiadiazolyl[1,3,4]),(2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl).

When the R₇ group is optionally substituted by a heterocyclic ring suchas imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, theheterocyclic ring itself may be optionally substituted by R₈ either onan available nitrogen or carbon atom, such as 1-(R₈)-2-imidazolyl,1-(R₈)-4-imidazolyl, 1-(R₈)-5-imidazolyl, 1-(R₈)-3-pyrazolyl,1-(R₈)-4-pyrazolyl, 1-(R₈)-5-pyrazolyl, 1-(R₈)-4-triazoly, or1-(R₈)-5-triazolyl. Where applicable, the ring may be substituted one ormore times by R₈.

Preferred are those compounds of the Formula (I) wherein R₁ is—CH₂-cyclopropyl, —CH₂—C₅₋₆ cycloalkyl, —C₄₋₆ cycloalkyl,tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or —C₁₋₂ alkyloptionally substituted by 1 or more fluorines, and —(CH₂)₂₋₄ OH; R₂ ismethyl or fluoro-substituted alkyl, R₃ is CN or C≡CR₈; and X is YR₂.

Most preferred are those compounds wherein R₁ is —CH₂-cyclopropyl,cyclopentyl, methyl or CF₂H; R₃ is CN; X is YR₂; Y is oxygen; X₂ isoxygen; X₃ is hydrogen; and R₂ is CF₂H or methyl.

A preferred subgenus of the compounds of the Formula (I) is thecompounds of the Formula (Ia)

wherein:

R₁ is CH₂-cyclopropyl, CH₂—C₅₋₆ cycloalkyl optionally substituted by OH,C₄₋₆ cycloalkyl, C₇₋₁₁ polycycloalkyl, (3- or 4-cyclopentenyl), phenyl,tetrahydrofuran-3-yl, benzyl or C₁₋₂ alkyl optionally substituted by 1or more fluorines,—(CH₂)₁₋₃C(O)O(CH₂)₀₋₂CH₃, —(CH₂)₁₋₃O(CH₂)₀₋₂CH₃, and—(CH₂)₂₋₄OH;

X is YR₂, halogen, nitro, NR₄R₅, or formyl amine;

X₄ is

X₅ is H, R₉, OR₈, CN, C(O)R₈, C(O)OR₈, C(O)NR₈R₈, or NR₈R₈;

Y is O or S(O)_(m′);

m′ is 0, 1, or 2;

R₂ is —CH₃ or —CH₂CH₃ optionally substituted by 1 or more halogens;

R₃ is hydrogen, C₁₋₄ alkyl, CH₂NHC(O)C(O)NH₂, halo-substituted C₁₋₄alkyl, CN, CH₂OR₈, C(Z′)H, C(O)OR₈, C(O)NR₈R₁₀, or C≡CR₈;

Z′ is O or NOR₈;

Z is C(O)R₁₄, C(O)OR₁₄, C(O)NR₁₀R₁₄, C(NR₁₀)NR₁₀R₁₄, CN, C(NOR₈)R₁₄,C(O)NR₈NR₈C(O)R₈, C(O)NR₈NR₁₀R₁₄, C(NOR₁₄)R₈, C(NR₈)NR₁₀R₁₄,C(NR₁₄)NR₈R₈, C(NCN)NR₁₀R₁₄, C(NCN)SR₉, (1-, 4- or5-{R₁₄}-2-imidazolyl), (1-, 4- or 5-{R₁₄}-3-pyrazolyl), (1-, 2- or5-{R₁₄}-4-triazolyl[1,2,3]), (1-, 2-, 4- or 5-{R₁₄}-3-triazolyl[1,2,4]),(1- or 2-{R₁₄}-5-tetrazolyl), (4- or 5-{R₁₄}-2-oxazolyl), (3- or4-{R₁₄}-5-isoxazolyl), (3-{R₁₄}-5-oxadiazolyl[1,2,4]),(5-{R₁₄}-3-oxadiazolyl[1,2,4]), (5-{R₁₄}-2-oxadiazolyl[1,3,4]),(5-{R₁₄}-2-thiadiazolyl[1,3,4]), (4- or 5-{R₁₄}-2-thiazolyl), (4- or5-{R₁₄}-2-oxazolidinyl), (4- or 5-{R₁₄}-2-thiazolidinyl), (1-, 4- or 5-{R₁₄}-2-imidazolidinyl);

R₇ is —(CR₄R₅)_(q)R₁₂ or C₁₋₆ alkyl wherein the R₁₂ or C₁₋₆ alkyl groupis optionally substituted one or more times by C₁₋₂ alkyl optionallysubstituted by one to three fluorines, —F, —Br, —Cl, —NO₂, —NR₁₀R₁₁,—C(O)R₈, —C(O)OR₈, —OR₈, —CN, —C(O)NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —OC(O)R₈,—NR₁₀C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀C(O)OR₉, —NR₁₀C(O)R₁₃,—C(NR₁₀)NR₁₀R₁₁, —C(NCN)NR₁₀R₁₁, —C(NCN)SR₉, —NR₁₀C(NCN)SR₉,—NR₁₀C(NCN)NR₁₀R₁₁, —NR₁₀S(O)₂R₉, —S(O)_(m′)R₉, —NR₁₀C(O)C(O)NR₁₀R₁₁,—NR₁₀C(O)C(O)R₁₀, thiazolyi, imidazolyl, oxazolyl, pyrazolyl, triazolyl,or tetrazolyl;

q is 0, 1, or 2;

R₁₂ is C₃-C₇ cycloalkyl, (2-, 3- or 4-pyridyl), (1- or 2-imidazolyl),piperazinyl, morpholinyl, (2- or 3-thienyl), (4- or 5-thiazolyl), orphenyl;

the dotted line formula (a) represents a single or double bond;

R₈ is independently selected from hydrogen or R₉;

R₉ is C₁₋₄ alkyl optionally substituted by one to three fluorines;

R₁₀ is OR₈ or R₁₁;

R₁₁ is hydrogen or C₁₋₄ alkyl optionally substituted by one to threefluorines; or when R₁₀ and R₁₁ are as NR₁₀R₁₁ they may together with thenitrogen form a 5 to 7 membered ring optionally containing at least oneadditional heteroatom selected from O, N, or S;

R₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl,oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings isconnected through a carbon atom and each may be unsubstituted orsubstituted by one or two C₁₋₂ alkyl groups;

R₁₄ is hydrogen or R₇; or when R₁₀ and R₁₄ are as NR₁₀R₁₄ they maytogether with the nitrogen form a 5 to 7 membered ring optionallycontaining one or more additional heteroatoms selected from O, N, or S;

provided that:

a) when R₁₂ is N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, orN-morpholinyl, then q is not 1; or

b) when R₁ is CF₂H or CF₃, X is F, OCF₂H, or OCF₃, X₅ is H, Z isC(O)OR₁₄ and R₁₄ is C₁₋₇ unsubstituted alkyl, then R₃ is other than H;

or the pharmaceutically acceptable salts thereof.

The most perferred compounds of Formula (I) are:

methyl4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate;

4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylicacid;

methylcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate];

methyltrans-[4-cyano-4-(3-cyclopentyloxy4-methoxyphenyl)cyclohexane-1-carboxylate];

methylcis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate];

methyltrans-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate];

cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid];

cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate],tris(hydroxymethyl)ammonium methane salt;

cis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylicacid];

trans-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid];

cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid];

trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid];methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate];

methyltrans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate];

methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylate];

methyltrans-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylate];

cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylicacid];

trans-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylicacid];

cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamide];

cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carboxamide];

trans-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carboxainide];

cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carbohydrazide];

cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-(2-acetylcarbohydrazide)];

cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(3-methyl[1,2,4]oxadiazol-5-yl)cyclohexane};

cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(2-methyl[1,3,4]oxadiazol-5-yl)cyclohexane};

cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(2-methyl[1,3,4]thiadiazol-5-yl)cyclohexane};

cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-1-tris(methylthio)methylcyclohexane];

methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-cyclohexane-1-carboxylate];

cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylicacid];

cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxamide];

methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxy-cyclohexane-1-carboxylate];

cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylicacid];

cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide];

trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxaldehyde];

methyltrans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylate];

trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylicacid];

methyltrans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylate];

trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylicacid];

trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide];

cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamicacid];

N-methyl-cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamicacid];

cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-N-(2-cyanoethyl)carboxamide];

cis-[1-(2-cyanoethyl)-5-{4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl}tetrazole];and

cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-(tetrazol-5-yl)cyclohexane].

As regards the compounds of Formula (II), the preferred compounds are asfollows:

When R₁ is an alkyl substituted by 1 or more halogens, the halogens arepreferably fluorine and chlorine, more preferably a C₁₋₄ alkylsubstituted by 1 or more fluorines. The preferred halo-substituted alkylchain length is one or two carbons, and most preferred are the moieties—CF₃, —CH₂F, —CHF₂, —CF₂CHF₂, —CH₂CF₃, and —CH₂CHF₂. Preferred R₁substitutents for the compounds of Formula (I) are CH₂-cyclopropyl,CH₂—C₅₋₆ cycloalkyl, C₄₋₆ cycloalkyl unsubstituted or substituted withOHC₇₋₁₁ polycycloalkyl, (3- or 4-cyclopentenyl), phenyl,tetrahydrofuran-3-yl, benzyl or C₁₋₂ alkyl unsubstituted or substitutedby 1 or more fluorines, —(CH₂)₁₋₃C(O)O(CH₂)₀₋₂CH₃,—(CH₂)₁₋₃O(CH₂)₀₋₂CH₃, and —(CH₂)₂₋₄OH.

When R₁ term contains the moiety (CR₄R₅), the R₄ and R₅ terms areindependently hydrogen or alkyl. This allows for branching of theindividual methylene units as (CR₄R₅)_(n) or (CR₄R₅)_(m); each repeatingmethylene unit is independent of the other, e.g., (CR₄R₅)_(n) wherein nis 2 can be —CH₂CH(—CH₃)—, for instance. The individual hydrogen atomsof the repeating methylene unit or the branching hydrocarbon canunsubstituted or be substituted by fluorine independent of each other toyield, for instance, the preferred R₁ substitutions, as noted above.

When R₁ is a C₇₋₁₁ polycycloalkyl, examples are bicyclo[2.2.1]-heptyl,bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1.0^(2,6)]decyl,etc. additional examples of which are described in Saccamano et al., WO87/06576, published Nov. 5, 1987.

W is preferably alkyl, alkenyl or alkynyl of 3 to 5 carbon atoms, andwhere it is alkenyl or alkynyl, that one or two double or triple bondsbe present. It is most preferred that W is ethynyl or 1,3-butadiynyl.

Z is preferably OR₁₄, OR₁₅, SR₁₄, S(O)_(m′)R₇, S(O)₂NR₁₀R₁₄, NR₁₀R₁₄,NR₁₄C(O)R₉, NR₁₀C(O)R₁₄, NR₁₀C(O)OR₇, NR₁₀C(O)NR₁₀R₁₄, NR₁₀S(O)₂NR₁₀R₁₄,NR₁₀C(NCN)NR₁₀R₁₄, NR₁₀S(O)₂R₇, NR₁₀C(CR₄NO₂)NR₁₀R₁₄, NR₁₀C(NCN)SR₉,NR₁₀C(CR₄NO₂)SR₉, NR₁₀C(NR₁₀)NR₁₀R₁₄, NR₁₀C(O)C(O)NR₁₀R₁₄, orNR₁₀C(O)C(O)OR₁₄.

Preferred X groups for Formula (I) are those wherein X is YR₂ and Y isoxygen. The preferred X₂ group for Formula (Ia) is that wherein X₂ isoxygen. The preferred X₃ group for Formula (I) is that wherein X₃ ishydrogen. Preferred R₂ groups, where applicable, is a C₁₋₂ alkylunsubstituted or substituted by 1 or more halogens. The halogen atomsare preferably fluorine and chlorine, more preferably fluorine. Morepreferred R₂ groups are those wherein R₂ is methyl, or thefluoro-substituted alkyls, specifically a C₁₋₂ alkyl, such as a —CF₃,—CHF₂, or —CH₂CHF₂ moiety. Most preferred are the —CHF₂ and —CH₃moieties.

Preferred R₇ moieties include unsubstituted or substituted —(CH₂)₀₋₂(2-,3- or 4-pyridyl), (CH₂)₁₋₂(2-imidazolyl), (CH₂)₂(4-morpholinyl),(CH₂)₂(4-piperazinyl), (CH₂)₁₋₂(2-thienyl), (CH₂)₁₋₂(4-thiazolyl),unsubstituted or substituted pyrimidinyl, and substituted orunsubstituted (CH₂)₀₋₂phenyl.

Preferred rings when R₁₀ and R₁₁ in the moiety —NR₁₀R₁₁ together withthe nitrogen to which they are attached form a 5 to 7 membered ringcomprised of carbon or carbon and at least one heteroatom selected fromO, N, or S include, but are not limited to 1-imidazolyl,2-(R₈)-1-imidazolyl, 1-pyrazolyl, 3-(R₈)-1-pyrazolyl, 1-triazolyl,2-triazolyl, 5-(R₈)-1-triazolyl, 5-(R₈)-2-triazoly 5-(R₈)-1-tetrazolyl,5-(R₈)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl, morpholinyl,piperazinyl, 4-(R₈)-1-piperazinyl, or pyrrolyl ring.

Preferred rings when R₁₀ and R₁₄ in the moiety —NR₁₀R₁₄ together withthe nitrogen to which they are attached may form a 5 to 7 membered ringcomprised of carbon or carbon and at least one heteroatom selected fromO, N, or S include, but are not limited to 1-imidazolyl, 1-pyrazolyl,1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl,piperazinyl, and pyrrolyl. The respective rings may be additionallysubstituted, where applicable, on an available nitrogen or carbon by themoiety R₇ as described herein for Formula (I). Illustrations of suchcarbon substitutions includes, but is not limited to,2-(R₇)-1-imidazolyl, 4-(R₇)-1-imidazolyl, 5-(R₇)-1-imidazolyl,3-(R₇)-1-pyrazolyl, 4-(R₇)-1-pyrazolyl, 5-(R₇)-1-pyrazolyl,4-(R₇)-2-triazolyl, 5-(R₇)-2-triazolyl, 4-(R₇)-1-triazolyl,5-(R₇)-1-triazolyl, 5-(R₇)-1-tetrazolyl, and 5-(R₇)-2-tetrazolyl.Applicable nitrogen substitution by R₇ includes, but is not limited to,1-(R₇)-2-tetrazolyl, 2-(R₇)-1-tetrazolyl, 4-(R₇)-1-piperazinyl. Whereapplicable, the ring may be substituted one or more times by R₇.

Preferred groups for NR₁₀R₁₄ which contain a heterocyclic ring are5-(R₁₄)-1-tetrazolyl, 2-(R₁₄)-1-imidazolyl, 5-(R₁₄)-2-tetrazolyl,4-(R₁₄)-1-piperazinyl, or 4-(R₁₅)-1-piperazinyl.

Preferred rings for R₁₃ include (2-, 4- or 5-imidazolyl), (3-, 4- or5-pyrazolyl), (4- or 5-triazolyl[1,2,3]), (3- or 5-triazolyl[1,2,4]),(5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]), (2-thiadiazolyl[1,3,4]),(2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl).

When the R₇ group is unsubstituted or substituted by a heterocyclic ringsuch as imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, theheterocyclic ring itself may be unsubstituted or substituted by R₈ on anavailable nitrogen or carbon atom, such as 1-(R₈)-2-imidazolyl,1-(R₈)-4-imidazolyl, 1-(R₈)-5-imidazolyl, 1-(R₈)-3-pyrazolyl,1-(R₈)-4-pyrazolyl, 1-(R₈)-5-pyrazolyl, 1-(R₈)-4-triazolyl, or1-(R₈)-5-triazolyl. Where applicable, the ring may be substituted one ormore times by R₈.

Preferred are those compounds of Formula (II) wherein R₁ is—CH₂-cyclopropyl, —CH₂—C₅₋₆ cycloalkyl, —C₄₋₆ cycloalkyl unsubstitutedor substituted by OH, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl),benzyl or —C₁₋₂ alkyl unsubstituted or substituted by 1 or morefluorines, and —(CH₂)₂₋₄ OH; R₂ is methyl or fluoro-substituted alkyl, Wis ethynyl or 1,3-butadiynyl; R₃ is R₇ where R₇ is an unsubstituted orsubstituted aryl or heteroaryl ring, X is YR₂, and Z is OR₁₄, OR₁₅,NR₁₀R₁₄, or NR₁₄C(O)R₉.

Most preferred are those compounds of Formula (II) wherein R₁ is—CH₂-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF₂H; Xis YR₂; Y is oxygen; X₂ is oxygen; X₃ is hydrogen; and R₂ is CF₂H ormethyl, W is ethynyl or 1,3-butadiynyl, and R₃ is a substituted orunsubstituted pyrimidinyl ring.

The most preferred compounds of Formula (II) are:

cis-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-ol],

cis-[4-(2-aminopyrimidin-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-ol],

trans-[4-(2-acetamidopyrimidin-5-ylethynyl)-4-(3-cyclopentyloy-4-methoxyphenyl)cyclohexan-1-ol],

trans-[4-(2-aminopyrmidin-5-yl-ethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-ol,

cis-[4-(2-methylaminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-ol],

cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-4-ylethynyl)cyclohexan-1-ol],

cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexan-1-ol],

cis-[4-(4-cyanothien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-ol],

cis-[4-(thiazol-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-ol],

cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[4-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexan-1-ol],

cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3-methyl[1,2,4]oxadiazol-5-yl)phenyl]ethynyl)cyclohexan-1-ol],

cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[1,3,4]oxadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-ol],

cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[1,2,4]oxadiazol-3-yl)phenyl]ethynyl)cyclohexan-1-ol],

cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[3-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)phenylethynyl)cyclohexan-1-ol,

cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[3-(5-methyl-[1,3,4]thiadiazol-2-yl)phenylethynyl]cyclohexan-1-ol,

trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexyl-1-amine],

trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexyl-1-formarnide],

trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-1-amine],cyclohexylsulfamate salt

cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexyl-1-amine],

cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexyl-1-formamide],

cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-1-amine],cyclohexylsulfamate salt,

trans-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl-1-amine],cyclohexylsulfamate salt, or

cis-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl-1-amine],cyclohexylsulfamate salt.

Some compounds of Formula (l) and Formula (II) may exist in both racemicand optically active forms; some may also exist in distinctdiastereomeric forms possessing distinct physical and biologicalproperties. All of these compounds are considered to be within the scopeof the present invention. Therefore another aspect of the presentinvention is the administration of either a racemate, a singleenantiomeric form, a single diastereomeric form, or mixtures thereof.

The terms cis and trans denote stereochemistry at the C-1 position ofthe cyclohexane ring relative to the R₃ group at the C-4 position.

The terms“C₁₋₃ alkyl”, “C₁₋₄ alkyl”, “C₁₋₆ alkyl” or “alkyl” includeboth straight or branched chain radicals of 1 to 10, unless the chainlength is limited thereto, including, but not limited to methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and thelike. “Alkenyl” includes both straight or branched chain radicals of 1to 6 carbon lengths, unless the chain length is limited thereto,including but not limited to vinyl, 1-propenyl, 2-propenyl, 2-propynyl,or 3-methyl-2-propenyl. “Cycloalkyl” or “cycloalkyl alkyl” includesgroups of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl,cyclopentyl, or cyclohexyl. “Aryl” or “aralkyl”, unless specifiedotherwise, means an aromatic ring or ring system of 6-10 carbon atoms,such as phenyl, benzyl, phenethyl, or naphthyl. Preferably the aryl ismonocyclic, i.e, phenyl. The alkyl chain includes both straight orbranched chain radicals of 1 to 4 carbon atoms. “Heteroaryl” as usedherein, is meant an aromatic ring system containing one or moreheteroatoms, such as imidazolyl, triazolyl, oxazolyl, pyridyl,pyrimidyl, pyrazolyl, pyrrolyl, furanyl, or thienyl. “Halo” as usedherein is meant all halogens, i.e., chloro, fluoro, bromo, or iodo.

Methods of Preparation

The preparation of compounds of Formula (I) is fully set forth in U.S.Pat. No. 5,552,438 issued Sep. 3, 1996. This patent is incorporatedherein in its entirety by reference as if fully set out herein. Thecompounds of Formula (II) are known compound and can be prepared by themethods set out in published PCT application PCT/US95/16711 published asWO96/19988 on Jul. 4, 1996 or PCT/US96/08080 published as WO96/38150 onDec. 5, 1996. The contents of these published PCT applications areincorporated herein by reference as if fully set forth herein.

Methods of Treatment

In order to use a compound of Formula (I) and (II) or a pharmaceuticallyacceptable salt thereof for the treatment of COPD, it will be formulatedin accordance with standard pharmaceutical practice as a pharmaceuticalcomposition. The compounds of Formula (I) and (II) or a pharmaceuticallyacceptable salt, polymorph, hydrate, etc., thereof can be used in themanufacture of a medicament for the prophylatic or therapeutic treatmentof COPD.

The pharmaceutical composition of the present invention will comprise aneffective, non-toxic amount of a compound of Formula (I) or (II) and apharmaceutically acceptable carrier or diluent. The compounds of Formula(I) and (II) are administered in conventional dosage forms prepared bycombining a compound of Formula (I) and (II) in an amount sufficient toreduce COPD symptoms and/or its progression, with standardpharmaceutical carriers according to conventional procedures. Theseprocedures may involve mixing, granulating, and compressing ordissolving the ingredients as appropriate to the desired preparation.

Thus, if a solid carrier is used, the preparation can be tableted,placed in a hard gelatin capsule in powder or pellet form, or in theform of a troche or lozenge. The amount of solid carrier will varywidely but preferably will be from about 25 mg to about 1 gram. When aliquid carrier is used, the preparation will be in the form of a syrup,emulsion, soft gelatin capsule, sterile injectable liquid such as anampule or nonaqueous liquid suspension. Where the composition is in theform of a capsule, any routine encapsulation is suitable, for exampleusing the aforementioned carriers in a hard gelatin capsule shell. Wherethe composition is in the form of a soft gelatin shell capsule anypharmaceutical carrier routinely used for preparing dispersions orsuspensions may be considered, for example aqueous gums, celluloses,silicates, or oils and are incorporated in a soft gelatin capsule shell.A syrup formulation will generally consist of a suspension or solutionof the compound or salt in a liquid carrier for example, ethanol,glycerine, or water with a flavoring or coloring agent.

The daily dosage regimen for oral administration is suitably about 0.001mg/kg to 100 mg/kg, preferably 0.01 mg/Kg to 40 mg/Kg, of a compound ofFormula (I) and (II) or a pharmaceutically acceptable salt thereofcalculated as the free base. The active ingredient may be administeredfrom 1 to 6 times a day, sufficient to exhibit activity.

While it is possible for an active ingredient to be administered neat,it is preferable to present it as a pharmaceutical formulation. Theactive ingredient may comprise, for topical administration, from 0.001%to 10% w/w, e.g., from 1% to 2% by weight of formulation, although itmay comprise as much as 10% w/w but preferably not in excess of 5% w/wand more preferably from 0.1% to 1% w/w of Formulation.

It will be recognized by one of skill in the art that the form andcharacter of the pharmaceutically acceptable carrier or diluent isdictated by the amount of active ingredient with which it is to becombined, the route of administration, and other well-known variables.

Formulations of the present invention comprise an active ingredienttogether with one or more acceptable carrier(s) thereof and optionallyany other therapeutic ingredient(s). The carrier(s) must be ‘acceptable’in the sense of being compatible with the other ingredients ofFormulation and not deleterious to the recipient thereof.

The preferred pharmaceutical formulation is an oral formulation and onewhich contains between about 1 mg and 60 mg of a compound of formula (I)or formula (II) at least once a day to a patient suffering from COPD orwho is at risk for developing COPD. Perferably the formulation will be atablet or similar solid dosage form such as an immediate release tablet.The more preferred formulation is a tablet which contains Formula (I) orFormula (II) in an amount of 5 mg, 10 mg, 15 mg or 20 mg. Mostperferably the formulation will be an immediate release tablet whichcontain about 15 mg of a compound; perferably the compound will becis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid]; or a pharmaceutically acceptable salt, polymorph, pro-drug, orhydrate thereof.

This invention relates to a method for treating COPD in a humansuffering from COPD, or for preventing or reducing the intensity of theonset of COPD in a human, by administering at least once daily apharmaceutical composition containing a compound of Formula (I) orFormula (II) in an amount between 1 mg and 20 mg admixed with apharmaceutically acceptable excipient. More preferably the methodscomprise administering a composition which contains 5 mg, 10 mg, 15 mgor 20 mg at least twice daily. Most preferably the compound will containabout 15 mg ofcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid]; or a pharmaceutically acceptable salt, polymorph, or hydratethereof and will be administered twice daily. And perferably thecomposition will be administered as a tablet and will be administeredorally.

EXAMPLE 1 Tablet Formulation

A tablet was prepared as described further herein using as the activeingredientcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid] and the excipients listed in Table 1.

TABLE 1 Ingredient Quantity (mg/tablet)cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl) 15.0cyclohexane-1-carboxylic acid]; Lactose monohydrate 103.0Microcrystalline cellulose 70.0 Sodium starch glycolate 10.0 Magnesiumstearate 2.0 Opadry Yellow OY-S-22907 5.0 Purified water purified wateris removed by drying q.s. during the application of the coatingsuspension. AFC Tablet Weight 205 Tablet shape octagonal

The ingredients are separately weighed and screened. The activeingredient is mixed with lactose monohydrate, microcrystalline celluloseand sodium starch glycolate. Magnesium stearate is added to the mixture.The blend is compressed and the tablet cores are coated with an aqueousfilm coat.

Blending

Initial step: Weigh the acid, lactose, microcrystalline cellulose,sodium starch glycolate and magnesium stearate. Screen each ingredientto de-aggregate using a vibratory/shaker separator or equivalent, fittedwith a suitable sieve screen.

Step 2: Charge a bin blender or equivalent with the microcrystallinecellulose, sodium starch glycolate, SB-207499 and lactose. Mix until ahomogeneous blend is achieved (approximately 20 minutes).

Step 3: Add the magnesium stearate to the blender. Blend forapproximately 3 minutes.

Compression and Coating

Step 1: Compress the tablets using a rotary tablet press or equivalent.

Step 2: Prepare a 12% w/w Opadry coating suspension, using 7.33 grams ofpurified water/gram of Opadry.

Step 3: Using a perforated pan coating system or equivalent, spray thecoating suspension on the tablet cores until the desired tablet weightgain is obtained.

Step 4: Dry the tablets.

No toxic effects are expected when these compounds are administered inaccordance with the present invention.

What is claimed is:
 1. A method for treating COPD, which methodcomprises administering to a mammal suffering from COPD an effectiveamount of a compound of Formula (I):

wherein: R₁ is —(CR₄R₅)_(n)C(O)O(CR₄R₅)_(m)R₆,—(CR₄R₅)_(n)C(O)NR₄(CR₄R₅)_(m)R₆, —(CR₄R₅)_(n)O(CR₄R₅)_(m)R₆, or—(CR₄R₅)_(r)R₆ wherein the alkyl moieties may be optionally substitutedwith one or more halogens; m is 0 to 2; n is 1 to 4; r is 0 to 6; R₄ andR₅ are independently selected from hydrogen or a C₁₋₂ alkyl; R₆ is C₃₋₆cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl moieties may be optionally substituted byOH, 1 to 3 methyl groups or one ethyl group; X is YR₂, halogen, nitro,NR₄R₅, or formyl amine; Y is O or S(O)_(m)′; m′ is 0, 1, or 2; X₂ is Oor NR₈; X₃ is hydrogen or X; X₄ is

X₅ is H, R₉, OR₈, CN, C(O)R₈, C(O)OR₈, C(O)NR₈R₈, or NR₈R₈; R₂ isindependently selected from the group consisting of —CH₃ and —CH₂CH₃optionally substituted by 1 or more halogens; s is 0 to 4; R₃ is CN; Zis C(Y′)R₁₄, C(O)OR₁₄, C(Y′)NR₁₀R₁₄, C(NR₁₀)NR₁₀R₁₄, CN, C(NOR₈)R₁₄,C(O)NR₈NR₈C(O)R₈, C(O)NR₈NR₁₀R₁₄, C(NOR₁₄)R₈, C(NR₈)NR₁₀R₁₄,C(NR₁₄)NR₈R₈ C(NCN)NR₁₀R₁₄, C(NCN)SR₉, (5-tetrazolyl), (3- or5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]), (2-thiadiazolyl[1,3,4]),wherein all of the heterocylic ring systems may be optionallysubstituted one or more times by R₁₄; the dotted line in formula (a)optionally represents a single or double bond; Y′ is ═O or ═S; R₇ is(CR₄R₅)_(q)R₁₂ or C₁₋₆ alkyl wherein the R₁₂ or C₁₋₆ alkyl group isoptionally substituted one or more times by, —F, —Br, —Cl, —NO₂,—NR₁₀R₁₁, —C(O)R₈, —C(O)OR₈, —OR₈, —CN, —C(O)NR₁₀R₁₁, —OC(O)NR₁₀R₁₁,—OC(O)R₈, —NR₁₀C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀C(O)OR₉, —C(NR₁₀)NR₁₀R₁₁,—C(NCN)NR₁₀R₁₁, —C(NCN)SR₉, —NR₁₀C(NCN)SR₉, —NR₁₀C(NCN)NR₁₀R₁₁,—NR₁₀S(O)₂R₉, —S(O)_(m′)R₉, —NR₁₀C(O)C(O)NR₁₀R₁₁, —NR₁₀C(O)C(O)R₁₀, orwherein the R₁₂ or C₁₋₆ alkyl group is optionally substituted one ormore times by C₁₋₂ alkyl optionally substituted by one to threefluorines; q is 0, 1, or 2; R₁₂ is C₃-C₇-cycloalkyl; R₈ is independentlyselected from hydrogen or R₉; R₉ is C₁₋₄ alkyl optionally substituted byone to three fluorines; R₁₀ is OR₈ or R₁₁; R₁₁ is hydrogen, or C₁₋₄alkyl optionally substituted by one to three fluorines; or when R₁₀ andR₁₁ are as NR₁₀R₁₁ they may together with the nitrogen form in a 5 to 7membered ring optionally containing at least one additional heteroatomselected from O/N/or S; R₁₄ is hydrogen or R₇; or the pharmaceuticallyacceptable salts thereof.
 2. The method of claim 1 wherein in Formula(I) R₁ is —CH₂-cyclopropyl, cyclopentyl, methyl or CF₂H; R₃ is CN; X isYR₂; Y is oxygen; X₂ is oxygen; X₃ is hydrogen; and R₂ is CF₂H ormethyl.
 3. The method of claim 2 wherein subject is a human and thecompound is: methyl4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate;4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylicacid; methylcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate];methyltrans-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate];methylcis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate];methyltrans-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate];cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate],tris(hydroxymethyl)ammonium methane salt;cis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylicacid];trans-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid];cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl,cyclohexane-1-carboxylicacid];trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid]; methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl-cyclohexane-1-carboxylate];methyltrans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate];methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylate];methyltrans-[4-cyano-4-(3-cyclopropylmethoxy4-difluoromelhoxyphenyl)cyclohexane-1-carboxylate];cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylicacid];trans-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylicacid];cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamide];cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carboxamide];trans-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carboxamide];cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carbohydrazide];cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-(2-cetylcarbohydrazide)];cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(3-methyl[1,2,4]oxadiazol-5-yl)cyclohexane};cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(2-methyl[1,3,4]oxadiazol-5-yl)cyclohexane};cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(2-methyl[1,3,4]thiadiazol-5-yl)cyclohexane};cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-1-tris(methylthio)methyleyclohexane];methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylate];cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylicacid];cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxamide];methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylate];cis-[4-cyano-4-(3-cyclopropyhnethoxy-4-methoxyphenyl)-1-metlhoxycyclohexane-1-carboxylicacid];cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxanide];trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-cyclohexane-1-carboxaldehyde];methyltrans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylate];trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylicacid]; methyltrans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylate];trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylicacid];trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide];cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamicacid];N-methyl-cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamicacid];cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-N-(2-cyanoethyl)carboxamide];cis-[1-(2-cyanoethyl)-5-{4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl}tetrazole];orcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-(tetrazol-5-yl)cyclohexane].4. The method of claim 1 wherein the subject is a human and the compoundiscis-[4-cyano-4(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid or a pharmaceutically acceptable salt or ester thereof.
 5. Themethod of claim 4 wherein the compound is administered at least twicedaily.
 6. The method of claim 5 wherein the compound is administeredtwice daily and at each time is administered in an amount between 1 mgand 20 mg.
 7. The method of claim 6 wherein the amount of compoundadministered at each time is 15 mg, is in tablet form and isadministered orally.
 8. A method for the phrophylatic treatment of amammal at risk for developing COPD, said method comprising administeringa composition comprising a compound of Formula (I) in an amount between1 and 60 mg admixed with a pharmaceutically acceptable excipient atleast once daily, wherein Formula (I) comprises:

wherein: R₁ is —(CR₄R₅)_(n)C(O)O(CR₄R₅)_(m)R₆,—(CR₄R₅)_(n)C(O)NR₄(CR₄R₅)_(m)R₆, —(CR₄R₅)_(m)O(CR₄R₅)_(m)R₆, or—(CR₄R₅)_(r)R₆ wherein the alkyl moieties may be optionally substitutedwith one or more halogens; m is 0 to 2; n is 1 to 4; r is 0 to 6; R₄ andR₅ are independently selected from hydrogen or a C₁₋₂ alkyl; R₆ is C₃₋₆cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl moieties may be optionally substituted byOH, 1 to 3 methyl groups or one ethyl group; X is YR₂, halogen, nitro,NR₄R₅, or formyl amine; Y is O or S(O)_(m)′; m′ is 0, 1, or 2; X₂ is Oor NR₈; X₃ is hydrogen or X; X₄ is

X₅ is H, R₉, OR₈, CN, C(O)R₈, C(O)OR₈, C(O)NR₈R₈, or NR₈R₈; R₂ isindependently selected from the group consisting of —CH₃ and —CH₂CH₃optionally substituted by 1 or more halogens; s is 0 to 4; R₃ is CN; Zis C(Y′)R₁₄, C(O)OR₁₄, C(Y′)NR₁₀R₁₄, C(NR₁₀)NR₁₀R₁₄, CN, C(NOR₈)R₁₄,C(O)NR₈NR₈C(O)R₈, C(O)NR₈NR₁₀R₁₄, C(NOR₁₄)R₈, C(NR₈)NR₁₀R₁₄,C(NR₁₄)NR₈R₈, C(NCN)NR₁₀R₁₄, C(NCN)SR₉, (5-tetrazolyl), (3- or5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]), (2-thiadiazolyl[1,3,4]),wherein all of the heterocylic ring systems may be optionallysubstituted one or more times by R₁₄; the dotted line in formula (a)optionally represents a single or double bond; Y′ is O or S; R₇ is—(CR₄R₅)_(q)R¹² or C₁₋₆ alkyl wherein the R₁₂ or C₁₋₆ alkyl group isoptionally substituted one or more times by —F, —Br, —Cl, —NO₂,—NR₁₀R₁₁, —C(O)R₈, —C(O)OR₈, —OR₈, —CN, —C(O)NR₁₀R₁₁, —OC(O)NR₁₀R₁₁,—OC(O)R₈, —NR₁₀C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀C(O)OR₉, —C(NR₁₀)NR₁₀R₁₁,—C(NCN)NR₁₀R₁₁, —C(NCN)SR₉, —NR₁₀C(NCN)SR₉, —NR₁₀C(NCN)NR₁₀R₁₁,—NR₁₀S(O)₂R₉, —S(O)_(m′)R₉, —NR₁₀C(O)C(O)NR₁₀R₁₁, —NR₁₀C(O)C(O)R₁₀, orwherein the R₁₂ or C₁₋₆ alkyl group is optionally substituted one ormore times by C₁₋₂ alkyl optionally substituted by one to threefluorines; q is 0, 1, or 2; R₁₂ is C₃₋₇ cycloalkyl,; R₈ is independentlyselected from hydrogen or R₉; R₉ is C₁₋₄ alkyl optionally substituted byone to three fluorines; R₁₀ is OR₈ or R₁₁; R₁₁ is hydrogen, or C₁₋₄alkyl optionally substituted by one to three fluorines; or when R₁₀ andR₁₁ are as NR₁₀R₁₁ they may together with the nitrogen form a 5 to 7membered ring optionally containing at least one additional heteroatomselected from O, N, or S; R₁₄ is hydrogen or R₇; or the pharmaceuticallyacceptable salts thereof.
 9. The method of claim 8 wherein in Formula(I) R₁ is —CH₂-cyclopropyl, cyclopentyl, methyl or CF₂H; R₃ is CN; X isYR₂; Y is oxygen; X₂ is oxygen; X₃ is hydrogen; and R₂ is CF₂H ormethyl.
 10. The method of claim 9 wherein the subject is a human and thecompound is methyl4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate;4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylicacid; methylcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate];methyltrans-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate];methylcis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate];methyltrans-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate];cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate],tris(hydroxymethyl)ammonium methane salt;cis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylicacid];trans-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid];cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid];trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid]; methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate];methyltrans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate];methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-ifluoromethoxyphenyl)cyclohexane-1-carboxylate];methyltrans-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylate];cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylicacid];trans-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylicacid];cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamide];cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carboxamide];trans-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carboxamide];cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carbohydrazide];cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-(2-cetylcarbohydrazide)];cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(3-methyl[1,2,4]oxadiazol-5-yl)cyclohexane};cis-{4-(3,4-bisdifluloromethoxyphenyl)-4-cyano-1-(2-methyl[1,3,4]oxadiazol-5-yl)cyclohexane};cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(2-methyl[1,3,4]thiadiazol-5-yl)cyclohexane};cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-1-tris(methylthio)methylcyclohexane];methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylate];cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylicacid]; SB 208970cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxanmide];methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylate];cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylicacid];cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide];trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-cyclohexane-1-carboxaldehyde];methyltrans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylate];trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylicacid]; methyltrans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylate];trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylicacid];trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide];cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamicacid];N-methyl-cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamicacid];cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-N-(2-cyanoetlhyl)carboxamide];cis-[1-(2-cyanoethyl)-5-{4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl}tetrazole];orcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-(tetrazol-5-yl)cyclohexane].11. The method of claim 9 wherein the subject is a human and thecompound iscis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid or a pharmaceutically acceptable salt or ester thereof.
 12. Themethod of claim 9 wherein the compound is administered at least twicedaily and at each time is administered in an amount between 1 mg and 20mg.
 13. The method of claim 9 wherein the compound is administered twicedaily and at each time is administered in an amount between 1 mg and 20mg.
 14. The method of claim 13 wherein the amount of compoundadministered at each time is 15 mg, is in tablet form, and isadministered orally.